Postpartum Hemorrhage in Women with Von Willebrand Disease after Enhanced Prophylactic Clotting Factor Suppletion: The Pregnancy and Inherited Bleeding Disorders Study (PRIDES)

Background: Pregnant women with von Willebrand Disease (VWD) are at a high risk for postpartum hemorrhage (PPH, ≥ 500 mL). To reduce the risk of severe PPH (≥ 1000 mL), pregnant women in the Netherlands with VWD receive prophylactic clotting factor suppletion based on their third trimester von Willebrand factor (VWF) activity and factor (F) VIII activity levels. Prior research showed a higher prevalence of severe PPH in women with VWD compared to the general Dutch population (13.3% versus 7.7%), leading to a revision of the Dutch guideline in 2018. The third trimester cut-off value for clotting factor suppletion was changed from < 50 IU/dL to < 80 IU/dL, and peak target VWF activity and FVIII levels during childbirth were increased from > 100 IU/dL to > 150 IU/dL. The change in the cut-off value and target peak clotting factor levels was initiated to aim for similar physiological VWF activity and FVIII levels as in the general population during childbirth, with the goal to reduce the incidence of (severe) PPH in women with VWD.

Aim: Assess the incidence of (severe) PPH in pregnant women with VWD, after implementation of the novel Dutch Hemophilia guideline in 2018.

Methods: The study design is a multicenter, observational cohort study in all six Dutch hemophilia treatment centers. All ongoing pregnancies > 10 weeks of gestation of women with VWD were eligible. Prophylactic VWF or VWF/FVIII concentrate was indicated during delivery for pregnancies with third trimester VWF or FVIII activity levels < 80 IU/dL. Baseline parameters, VWF activity/FVIII levels, blood count parameters, total vaginal blood loss < 24 hours postpartum, and obstetric risk factors were recorded.

Statistical analysis: we used descriptive statistics for baseline parameters, obstetric risk factors and delivery outcomes, including PPH incidence. Logistic regression was used for multivariate analysis, with primiparity, cesarean section and a history of PPH as possible confounders. Subgroup analysis was performed in those with and without indication for prophylactic clotting factor suppletion (third trimester levels < 80 IU/dL and ≥ 80 IU/dL).

Results: between September 2018 and March 2024, 160 deliveries in women with VWD were recorded, most from women with VWD type 1 (74.4%, n=119/160). Overall, 37.5% (n=60/160) were primipara. History of PPH was present in 28.7% (n=46/160). Cesarean section occurred in 23.1% (n=37/160). The incidences of PPH and severe PPH were 38.1% (n=61/160) and 18.1% (n=29/160), respectively. Median blood loss was 385 mL (IQR 200-700).

58.8% (n=94/160) deliveries had third trimester levels < 80 IU/dL and 93.6% (n=88/94) received prophylactic clotting factor suppletion during delivery. The ≥ 80 IU/dL group (n=66) received prophylaxis in 7.6% (n=5/66). Both groups had similar occurrences of a cesarean section (23.4%, n=22/94 and n=15/66, p-value 0.92) and primiparity (37.2%, n=35/94 and 37.9%, n=25/66, respectively). The < 80 IU/dL group had a lower incidence of a history of PPH (22.5%, n=24/94 vs. 33.3%, n=22/66), but this was not significant (p-value 0.26).

In the < 80 IU/dL group, the PPH incidence was 41.5% (n=39/94) compared to 33.3% (n=22/66) in the ≥ 80 IU/dL group (p-value 0.30). Multivariate analysis showed no difference in PPH incidence when adjusted for cesarean section, a history of PPH, and primiparity (adjusted OR 0.69, 95% CI 0.35-1.36). The incidence of severe PPH was similar in the < 80 IU/dL group (19.1%, n= 18/94) vs. the ≥ 80 IU/dL group (16.7%, n=11/66, p-value 0.69), with an adjusted OR of 0.84 (95% CI 0.36-1.91). Median blood loss was 360 mL (IQR 200-700, < 80 IU/dL) vs. 400 mL(IQR 250-685, ≥ 80 IU/dL group, p-value 0.97).

Conclusion: prophylactic clotting factor suppletion in women with VWD with third trimester VWF activity or FVIII levels < 80 IU/dL resulted in similar PPH and severe PPH incidences as in deliveries of women with VWD with ≥ 80 IU/dL without prophylaxis, when adjusted for obstetric risk factors. The overall incidence of PPH in women with VWD remains high.

Future analysis: Upcoming analysis focusses on comparing the subgroups with third trimester levels < 50 IU/dL and between 50-80 IU/dL who received more intensive clotting factor supplementation with data from a cohort study on PPH in women with VWD during the six years prior to the guideline revision. In addition, the incidence of PPH and obstetric risks factors in the general Dutch population during the same period as the PRIDES study will be compared.

Eikenboom:CSL Behring: Research Funding. Kruip:Bristol Myers Squibb: Speakers Bureau; Roche: Speakers Bureau; Sobi: Research Funding, Speakers Bureau. Punt:CSL Behring: Current Employment. Coppens:F. Hoffman-La Roche: Research Funding; Spark Therapeutics: Honoraria; Novo Nordisk: Research Funding; Pfizer: Honoraria; CSL Behring: Honoraria, Research Funding; Octapharma: Honoraria; Sobi: Honoraria, Research Funding; European Association for Haemophilia and Allied Disorders (EAHAD): Other: Non-financial conflicts of interest: Member of the gene therapy working group of the European Association for Haemophilia and Allied Disorders (EAHAD); Bayer: Honoraria, Research Funding. Moenen:Octapharma: Research Funding; Bayer: Research Funding. Peters:Pfizer: Research Funding. Schutgens:Takeda: Research Funding; Sobi: Research Funding; Roche: Research Funding; Octapharma: Research Funding; Novo Nordisk: Research Funding; Novartis: Research Funding; Hemab: Research Funding; CSL Behring: Research Funding; Bayer: Research Funding. Van Galen:Octapharma: Research Funding.